Bordetella pertussis infection is causative agent of whooping cough, with an estimated number of 60 millions cases each year, killing approximately 355,000 people worldwide annually (WHO), in particular children and immune compromised individuals. Although treatment with antibiotics is available (erythromycin), by the time the disease is diagnosed, bacterial toxins have often caused severe damage. Prevention of the disease is therefore of great importance. The prime means of control remains vaccination. Conventionally, vaccines against pertussis (“whooping-cough”) infections have been based on whole cells of B. pertussis. Whole cell Bordetella pertussis vaccines, comprising whole bacteria that have been killed by heat treatment, formalin or other means, have been included in general vaccination programs since the early 1950's.
Immunization with the whole-cell pertussis vaccine, while effective at preventing whooping cough in infants, has been associated with local, systemic and neurological reactions, including fevers, convulsions and encephalopathy in children. LPS is responsible for the major part of the adverse reactions in children following pertussis immunization. During bacterial infections of animals, LPS or its lipid A moiety activates the innate immune system through interaction with Toll-like receptors, primarily TLR-4. The host response to lipid A includes the production of cationic antimicrobial peptides, cytokines, chemokines and additional immunostimulatory molecules. In limited infections, the response to lipid A helps to clear the bacteria, but in overwhelming sepsis, high levels of circulating cytokines and procoagulant activity may damage the microvasculature and precipitate the syndrome of Gram-negative septic shock with disseminated intravascular coagulation.
No conclusive evidence for a protective role of LPS in pertussis vaccines is available, although passive immunization experiments in mice have demonstrated that antibodies against LPS can confer a level of protection. In addition and more importantly, the presence of LPS in a vaccine however does provide adjuvant activity by enhancing the immune response against other antigens (K. Mills: Immunity to Bordetella pertussis. Microbes and Infection 3: 655-677 (2001).
Concerns about safety have adversely affected vaccine uptake and have motivated the development of acellular pertussis vaccines, prepared with highly purified antigens from B. pertussis. In recent years, besides the so-called “whole cell vaccines” or “WCV's”, also acellular vaccines or “ACVs” have now been introduced in several countries.
Acellular vaccines normally comprise of 1 to 3 or more antigens of the pathogenic organism. In the case of B. pertussis antigens commonly used are: pertussis toxin (PT, normally treated to destroy its toxicity while retaining immunogenicity), filamentous hemagglutinin (FHA), fimbriae, and the 69 kD protein or pertactin (Prn). In general the reactogenicity of acellular vaccine is much lower than the reactogenicity of whole cell vaccine. Acellular vaccine is associated with a significantly reduced frequency of systemic reactions (fever, vomiting, fretfulness, anorexia) and local reactions (swelling, redness, warmth, tenderness, stiffness, pain). However, the clinical data are still controversial whether the protective immunity of acellular vaccines matches the protective effect of whole cell vaccine. In many studies the protective effect of whole cell vaccines is superior and a debate is ongoing whether this outweighs the risk of rare but serious adverse effects of whole cell vaccines in infants. Currently various immunizations schemes are being tested, wherein up to six doses of acellular vaccine are given. The whole cell vaccine was initially given 5 times, incorporated with the routine vaccines schedule with the last booster given between 4-6 years of age. The acellular pertussis vaccine is now recommended to be given 6 times including a last dose (combined with the diphtheria-tetanus vaccine) during the teenage years. The acellular vaccine appears to be safer than the whole cell-based vaccine, but both should not be given to children with a previous allergic reaction to the pertussis vaccine
The adverse side effects of pertussis whole cell vaccines have been well documented in the art (review: S. H. Yeh: Pertussis: persistent pathogen, imperfect vaccines. Expert Rev. Vaccines 2: 113-127 (2003). Although currently used acellular vaccines in part overcome these adverse side effects, the protective immunity provided by these vaccines is still controversial and leaves much room for improvement. Importantly, in a mouse model superior long-term protection was found with whole-cell as compared to acellular vaccines (K. Mills: Immunity to Bordetella pertussis. Microbes and Infection 3: 655-677 (2001)). Moreover, acellular vaccines are more costly and difficult to produce, requiring isolation, extensive purification and quality control of various antigens and mixing and formulating them in optimal/desired quantities. There is clearly a long felt need for better B. pertussis, B. parapertussis, B. bronchiseptica and other Gram negative vaccines.